This invention relates to a mixture of a starch and an excipient for tabletting wherein the starch is free-flowing compressible processed starch powder suitable for use both as a binder and as a disintegrant in tablets. The free-flowing starch powder improves the characteristics and the properties of the tablets when mixed with one or more different excipients.
The present invention also discloses a method for obtaining tablets comprising the free-flowing compressible processed starch together with at least one excipient and the tablets obtained by such a method.
Tablets are one of the most frequently employed delivery forms for most medicinal preparations. This situation can be explained by the fact that this dosage form allows a good accuracy of dosage of the active component of the medicinal formulation. Furthermore handling and packaging are a lot easier and conservation and stability of these preparations are generally better than those of other formulations.
The same arguments also explain the reason why tablets are often used as media for other applications such as food, including confectionery products, aromas or sweeteners, detergents, dyes or phytosanitary products.
Tablets can be manufactured using three main processes, wet granulation, dry granulation and direct compression.
In wet granulation, components are typically mixed and granulated using a wet binder, the wet granulates are then sieved, dried and eventually ground prior to compressing the tablets.
In dry granulation, powdered components are typically mixed prior to being compacted, also called pre-compression, to yield hard slugs which are then ground and sieved before the addition of other ingredients and final compression.
Direct compression is now considered to be the simplest and the most economical process for producing tablets. This process requires only two steps; i.e., the mixing of all the ingredients and the compression of this mixture.
A component of a tablet is usually defined as being either an excipient or an active ingredient. Active ingredients are normally ones that trigger a pharmaceutical, chemical or nutritive effect and they are present only up to the strict limit necessary for providing this effect in the right proportion. Excipients are chemically and pharmaceutically inert ingredients that are included to facilitate the preparation of the dosage forms or to adapt the release of the active ingredients.
Excipients can be characterised according to their function during the formulation as, for instance, binders, disintegrants, fillers (or diluents), glidants, lubricants and eventually flavours, sweeteners and dyes.
Lubricants are intended to improve the ejection of the compressed tablet from the die of the tablet-making equipment.
Glidants are added to improve the powder flow. They are typically used to help the mixture of all the components to fill evenly and regularly the die before the compression.
Fillers are inert ingredients sometimes used as bulking agents in order to decrease the concentration of the active ingredient in the final formulation. The binders in many cases also provide the function of filler.
Disintegrants may be added to formulations in order to help the tablets disintegrate when they are placed in a liquid environment and so release the active ingredient. The disintegration properties are, mostly, based upon the ability of the disintegrant to swell in the presence of a fluid, such as water or gastric juice. This swelling disrupts the continuity of the tablet structure and thus, allows the different components to enter into solution or into suspension. Commonly used disintegrants include native starches, modified starches, modified cellulose, microcrystalline cellulose or alginates.
Binders are used to hold together the structure of the dosage forms. They have the property to bind together all the other ingredients after sufficient compression forces have been applied and they provide the integrity of the tablets.
Starches are known to act in some cases as binders and in some other cases as disintegrants according to the fact that they are native, chemically modified or physically modified.
Native granular starches and, to a smaller extent, cooked starches (also referred to as pregelatinised starches) can show somewhat limited binding capacities when employed in direct compression. Cooked starches, even when they are satisfactory as binders are not satisfactory in terms of disintegration. These starches do not really disperse, they show the tendency to prevent the penetration of water into the tablet, thus preventing its disintegration, by forming a tacky film on its surface.
EP-A-0402186 describes a directly compressible starch mixture obtained by mixing 1 to 20% of a starch paste with 99-80% of native starch. The starch paste is obtained by treating native starch at 85xc2x0 C., which results in breaking of the starch granules.
Partially cold water swellable starches for use as binders and/or disintegrants in the manufacture of tablets by direct compression and as fillers for formulations supplied in hard gelatine capsules, are described in U.S. Pat. No. 3,622,677 and U.S. Pat. No. 4,072,535. The material described is essentially a pre-compacted starch powder obtained by subjecting a non-gelatinised granular starch to physical compaction between steel rollers with the possible input of thermal energy. The compacted starch shows the presence of sharp birefringent granules and non-birefringent granules as well as some aggregates of granules and fragments dried to a moisture content of 9-16%. After the compactation the starch is ground and sieved to yield a free-flowing powder. The above mentioned starch powders exhibit limited binding capacity in direct compression and poor disintegration properties. Formulations of active ingredients prepared using that kind of excipient are described, for instance in EP-A-0,130,683 for N-acetyl-p-aminophenol.
Other cold water swellable physically modified starches are described as being useful as disintegrant but with very poor binding properties (see U.S. Pat. No. 4,383,111). In that case, the granular starch is cooked in the presence of water and possibly an organic solvent at temperature not higher than 10xc2x0 C. higher than its gelatinisation temperature. The so-obtained starch is then dried resulting in non-birefringent granules. Mixtures containing cold water swellable starch are describe for food application i.e. U.S. Pat. No. 3,956,515 for the preparation of starch batter for meat pieces.
Chemical modification of starch has also been investigated. Crosslinked pregelatinised starches such as starch phosphates, starch adipates, starch sulphates, starch glycolates or carboxymethyl starches are useful as disintegrants although they exhibit poor binding capacities (see U.S. Pat. No. 3,034,911 and U.S. Pat. No. 4,369,308).
Acid and enzyme hydrolysed starches are reported to be useful as binders (U.S. Pat. No. 4,551,177). These compressible starches are prepared by treating a granular starch with an acid and/or alpha-amylase enzyme at a temperature below the gelatinisation temperature of the starch. These treated starches show altered and weakened granules with disrupted surfaces. These starches are said to be useful as binders for tabletting as well as binders and fillers for capsule filling and are said to exhibit reasonable disintegration properties.
Dextrinised starches (see U.S. Pat. No. 4,384,005) and starch fractions such as non-granular amylose (see U.S. Pat. No. 3,490,742) are also described as having limited binding and/or disintegration properties. These are of limited interest due to the expensive processes needed for their preparation.
Co-pending European patent application ep 99300571.9 describes a free-flowing directly compressible processed starch powder suitable for use as a binder in direct compression processes yielding very hard tablets at relatively low compression forces as well as for use as a binder and/or filler in the preparation of capsule dosage forms.
Tablets resulting from the compression of the above-mentioned starch disintegrate in an aqueous medium at a high speed and, additionally, exhibit a low friability pattern. This directly compressible starch powder is useful as a binder and/or a disintegrant for tablets prepared by direct compression, wet granulation or dry granulation. It is also useful as a binder and as a filler in the process of filling capsules.
This co-pending patent application is herein incorporated by reference.
The present invention discloses a composition for forming a tablet or other unit dosage form comprising regular and smooth partially-swollen non-birefrigent granules of starch, together with non-swollen birefrigent granules of starch wherein the ratio of non-swollen birefrigent granules to swollen non-birefrigent granules is in the range of from 1:5 to 5:1 and at last one other excipient. The other excipient may be a binder, filler or disintegrant. The starch typically has an average particle size greater than 50 xcexcm and a moisture content of from 3 to 15% by weight. To be of practical use the composition further comprises an active ingredient.
The active ingredient is present in an amount which is effective to perform its desired function and is typically present in an amount of from 0.01 to 80% (w/w).
The other excipient is at least one compound but it may be between 1 and 10. Typical excipients are chosen from the group consisting of starch, pregelatinised starch, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, calcium carbonate, calcium sulphate, lactose, dextrose, sucrose, sorbitol and mannitol or mixtures thereof.
The ratio of the directly compressible starch and the (other) excipient is dependent on the type of use one wants to make of the tablet typically it is between 1:10 and 10:1.
The present invention also discloses a method for obtaining tablets comprising the directly compressible processed starch together with the at least one (other) excipient.
The present inventions further discloses tablets comprising regular and smooth partially-swollen non-birefrigent granules of starch, together with non-swollen birefrigent granules of starch wherein the ratio of non-swollen birefrigent granules to swollen non-birefrigent granules is in the range of from 1:5 to 5:1 and at last one other excipient. Such tablets preferably contain an active ingredient.